A sensitive methenamine silver/Nissl stain was used to study the morphology and relationship of pre-plaques (presumed early senile plaques) in Down's syndrome brains to glial nuclei, capillaries and neuronal perikarya. The larger pre-plaques (greater than 50 microns) usually encompassed all of these tissue elements. However, the smaller pre-plaques (less than or equal to 50 microns) were almost always found immediately adjacent to, or around the cell bodies of neurons (often with associated satellite cells), and they failed to show any consistent, close spatial relationship to the other tissue components. Thus we consider an early stage of pre-plaque formation to be the deposition of amyloid adjacent to the cell body of a morphologically normal neuron. Based on the study of transitional forms, we suggest that the amyloid progressively accumulates around the cell body until the enclosed neuron degenerates. How these pre-plaque lesions might eventually develop into the typical plaque structure is uncertain. Our observations support the theory of a neuronal origin for plaque amyloid.